2-alkyl-3-haloisothiazol-3-thione

ABSTRACT

This disclosure relates to a novel class of 2-alkyl-3-haloisothiazolium salts. These salts have been found to be useful in controlling the growth of bacteria and fungi. They have also been found to be useful intermediates in the preparation of novel and known antibacterial and antifungal compounds.

RELATED U.S. APPLICATION DATA

This is a continuation of application Ser. No. 325,467, filed Nov. 27,1981, now abandoned, which is a divisional application of Ser. No.190,779, filed on Sept. 25, 1980, now U.S. Pat. No. 4,328,347, which isa divisional application of Ser. No. 952,038, filed on Oct. 16, 1978,now U.S. Pat. No. 4,281,136, which is a continuation-in-part of Ser. No.854,456, filed on Nov. 25, 1977, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Antibacterial and Antifungal Compositions

2. Prior Art

The 2-alkyl-3-haloisothiazolium salts of this invention are novelcompounds. The 2-alkyl-4-isothiazolin-3-thiones and2-alkyl-3-dicyanomethylene-4-isothiazolines produced therefrom are alsonovel.

The 2-alkyl-3-haloisothiazolium salts can be converted to2-alkyl-4-isothiazolin-3-ones. A number of these2-alkyl-4-isothiazolin-3-ones have been reported in the literature; U.S.Pat. No. 3,761,488; J. Heterocyclic Chem. 8, 571 (1971).

SUMMARY OF THE INVENTION

The novel 2-alkyl-3-haloisothiazolium salts disclosed herein can berepresented by the general formula: ##STR1## wherein:

R represents an alkyl or alkenyl group;

X represents a halogen, preferably chlorine or bromine;

Y and Z represent suitable substituents as defined herein; and

A⁻ represents a suitable anion as defined herein.

These novel salts are useful as antibacterial and antifungal agents andfind utility in paints, polymer emulsions, paper mills, industrialcooling water, agriculture, soaps, cutting oils, anionic surfactants,adhesives etc. They may be used alone or in admixture with otherantimicrobial agents.

The novel 2-alkyl-3-haloisothiazolium salts are also usefulintermediates in the maufacture of other valuable antimicrobial agents.These salts can be reacted with a variety of reagents to provide thetransformations which are illustrated as follows: ##STR2## wherein [O]is a suitable oxygen source and [S] is a suitable sulfur source asdescribed herein.

The 2-alkyl-3-haloisothiazolium salts of this invention are prepared byreacting the corresponding 3-haloisothiazoles with a suitable alkylatingagent as illustrated below. ##STR3## The starting 3-haloisothiazoles canbe prepared by methods known in the art (W. R. Hatchard, J. Org. Chem.,29, 660 (1964); S. Nakagawa, J. Okumura, F. Sakai, H. Hoshi and T.Naito, Tetrahederon Letters, 3719 (1970); R. P. Williams, U.S. Pat. No.3,285,390; and E. Mailey, U.S. Pat. No. 3,341,547).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The salts of formula I, more particularly the cations thereof, are theessence of this invention. They are useful to control the growth ofbacteria and, or fungi and they are useful intermediates in thesynthesis of other antibacterial and antifungal agents.

It is the cationic portion which is essential for the antimicrobialactivity demonstrated by the salts and it is the cationic portion thatis a precursor for the synthesis of other antimicrobial compounds.

The anionic portion of formula I is not critical and its sole purpose,insofar as is pertinent to this invention, is to neutralize the chargeof the cation. The nature of the anion does not materially effect theantimicrobial activity of the cation nor does the anion affect theutility of the salts as intermediates in the preparation of the otherantimicrobials II, III and IV. It is not impossible, however, that theanion might play a role in special applications where differences suchas stability, solubility or some unique physical property may besignificant or where the anion is a special negatively charged specieswhich itself has antimicrobial activity.

In formula I, X represents a halogen. While any halogen may be suitable,those salts wherein X is bromine or chlorine are preferred because oftheir economy and availability. Compounds wherein X is chlorine are themost economical and are especially preferred.

The substituents Y and Z can be the same or different. They arepreferably chosen from the group consisting of hydrogen, lower alkyl(e.g. methyl to butyl with methyl and ethyl being especially preferred)halogen (F, Cl, Br or I with Cl being especially preferred), cyano,carboalkoxy (e.g. carbomethoxy through carbobutoxy with carbomethoxy andcarboethoxy being especially preferred). While variation in Y and Z doappear to have some effect on the level of activity, that effect is oneof degree rather than one of kind. In all cases tested the level ofactivity exceeded the level desirable for commercial purposes. Thepreferences for one group over another, in the final analysis would mostprobably be governed by economic factors related to ease of synthesis,cost of materials etc.

The size of the R group is not critical. Any alkyl or alkenyl group isdeemed suitable. The groups may be normal or branched and may bealicyclic or cyclic. As a practical matter, groups having eight carbonsor less are preferred (e.g. alkyl groups from methyl to octyl andalkenyl groups from allyl to octenyl). Especially preferred are methylor ethyl since there are a number of commercially available alkylatingagents which are especially suitable for the preparation of the methyland ethyl analogs.

The anion A⁻ may be any suitable anion, its sole purpose being toneutralize the charge of the anion, i.e. as a gegen ion. This functioncould be satisfied by any negatively charged species which would notreact with and alter the cation. For example, simple anions such aschloride, bromide, iodide, sulfate, phosphate, carbonate etc. would besuitable.

As a practical matter, however, the anion is normally determined by thealkylating agent used. The most reactive alkylating agents such asdimethyl sulfate, diethyl sulfate, methyl fluorosulfonate,trimethyloxonium fluoroborate, triethyloxonium fluoroborate,trimethyloxonium hexachloroantimonate, n-propyl or n-octyltrifluoromethane sulfonate, trimethyloxonium hexafluorophosphate, methyltrifluoromethane sulfonate, allyl trifluoromethanesulfonate, etc. arepreferred, and these provide salts having anions such asfluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, tetrafluoroborate, etc.respectively.

The 2-alkyl-3-haloisothiazolium salts of this invention are prepared byquaternization of the corresponding 3-haloisothiazole with a suitablealkylating agent. It is preferred to use the most reactive alkylatingagents such as dimethyl sulfate, diethyl sulfate, methylfluorosulfonate, trimethyloxonium fluoroborate, triethyloxoniumfluoroborate, trimethyloxonium hexachloroantimonate, n-propyl or n-octyltrifluoromethane sulfonate, trimethyloxonium hexafluorophosphate, methyltrifluoromethane sulfonate, allyl trifluoromethanesulfonate, and thelike. Especially preferred are the commercially available agents such asdimethyl sulfate, diethyl sulfate, methyl fluorosulfate, methylfluorosulfonate, trimethyloxonium fluoroborate, triethyloxoniumfluoroborate and the like. Such reagents, known in the art, arepreferred since reactions utilizing them occur more rapidly and undermilder reaction conditions than those using less reactive alkylatingagents such as alkyl halides.

In the preferred process of this invention, the appropriate alkylatingagent and isothiazole are brought together and heated to a reactiontemperature that is sufficient to effect reaction. The relative amountsof the reactants are not critical and while equimolar amounts arenormally preferred, an excess of either reagent is suitable. It ispreferred to run the reaction without solvent, but a suitable reactioninsert solvent may be used if desired. (The choice of solvent is withinthe skill of the art, typical examples being methylene chloride,chloroform, ethylene dichloride, ethers such as ethyl ether, dibutylether, diphenyl ether, etc.)

The reaction temperature preferred varies with the relative reactivitiesof the reagents. They normally do not exceed reflux temperature of thereaction mixture. If the reaction temperature required exceeds theboiling point of the reaction mixture, or one of its components, it maybe necessary to achieve a higher temperature by running the reactionunder pressure in a sealed reaction vessel.

The maximum temperature need only be kept below the thermaldecomposition point of the reactants and product involved. Normally,temperatures are not lower than 0° C. nor higher than 250° C. When themore active alkylating agents are used, the preferred range is fromabout 25° C. to 150° C.

Parameters such as the temperature, reaction time etc. depend upon therelative reactivity of the specific reactants used. The reaction may becomplete in as short a time as two minutes, or require as long as fortyeight hours.

The salts produced can be purified if necessary by means known in theart. It is usually sufficient to merely wash out excess startingmaterials with an appropriate solvent such as toluene, benzene, ether,etc. and the like. If further purification is required the salts may berecrystallized from a suitable solvent.

As mentioned, the nature of the anion is immaterial for the applicationsof this invention with the possible exception certain specialapplications. If, for any reason, an anion is desired which differs fromthat normally determined by the alkylating agent, a simple exchangereaction can be run as illustrated below ##STR4##

Such an exchange is most thoroughly and efficiently accomplished when M⁺is the cationic portion of an ion exchange resin or M⁺ is chosen suchthat M⁺ A⁻ will precipitate from the solution while the resulting2-alkyl-3-haloisothiazolium salt will remain in solution. In theexamples there is provided an illustration wherein such an exchange iscarried out using silver nitrate as M⁺ Q⁻. In that case silverfluorosulfonate precipitated while the isothiazolium nitrate remained insolution.

While it is preferred to choose M⁺ Q⁻ so that either M⁺ A⁻ or the newisothiazolium salt produced will precipitate out of solution, theexchange could be effected by creating an equilibrium, removing thesolvent and separating the salts by methods known in the art, forexample recrystallization techniques. Quite obviously, mixtures of saltswherein the anions are different would also be suitable since muchmixtures would have the desired chemical and antimicrobial properties.

The number of inorganic or organic salts that could be used in such anexchange are countless, and it is expected that a chemist skilled in theart could choose a suitable reagent from among these. Such a chemistshould, of course, avoid reagents which could be expected to react withthe cation, for example an alkali hydroxide, an alkali sulfide etc. Suchexchange reactions are, insofar as is pertinent to this invention,merely illustrative of the ease with which a different anion may beintroduced if desirable for any reason.

As mentioned, the novel 2-alkyl-3-haloisothiazolium salts of thisinvention have two major uses. In addition to being useful in a varietyof media to inhibit growth of bacteria and fungi, they may be used asintermediates to prepare other antimicrobial agents such as2-alkyl-3-dicyanomethylene-4-isothiazolines,2-alkyl-4-isothiazolin-3-thiones and 2-alkyl-4-isothiazolin-3-ones.

The 2-alkyl-3-dicyanomethylene-4-isothiazolines are prepared asillustrated below: ##STR5## The groups R, X, Y, Z and A are aspreviously defined.

The conversion is very facile. It is preferred to simply mix themalononitrile with the 2-alkyl-3-halothiazolium salt in the presence ofa suitable polar solvent. As the product is formed it usuallyprecipitates from the reaction solvent and is isolated by methodscommonly employed in the art.

Neither temperature not time is critical. For convenience it ispreferred to run the reaction at room temperature, but reactiontemperatures from below 0° C. to above 100° C. would be suitable.

The reaction time may vary from 2 min to 12 hrs and would, of course,depend on the temperature.

Any solvent capable of solubilizing the salts such as ethanol, methanol,acetonitrile, and the like would be suitable.

As illustrated below, the 2-alkyl-3-haloisothiazolium salts provide aconvenient starting material for the novel2-alkyl-4-isothiazolin-3-thiones. ##STR6##

The suitable source of sulfur, [S], may be provided by a number ofreactants such as thiourea, sodium sulfide, sodium hydrosulfide, methylmercaptan, ethyl xanthate including analogs of the above such aspotassium sulfide, lithium sulfide, hydrogen sulfide, methyl throughoctyl mercaptans, methyl through octyl xanthates, methyl through octylthioureas and the like.

Again, the conversion is very facile. In the especially preferredprocess, it is simply necessary to mix thiourea with the2-alkyl-3-haloisothiazolium salt in the presence of a suitable polarsolvent. As the product is formed it normally precipitates from thereaction medium and can be collected by filtration.

Neither temperature nore time is critical. For convenience it ispreferred to carry out the reaction at room temperature, but reactiontemperatures from below 0° C. to above 100° C. would be suitable.

The reaction time may vary from 30 min to 12 hrs and would, of course,depend on the temperature.

The nature of the solvent is not critical and solvents capable ofdissolving the salt such as methanol, ethanol, acetonitrile and the likeare suitable.

Similarly, the 3-halo-2-alkylisothiazolium salts of the invention can bereacted with a suitable oxygen source to provide2-alkyl-4-isothiazolin-3-ones as shown below. ##STR7##

The reaction medhanism for the conversion of the2-alkyl-3-haloisothiazolium salts is not clear. It would appear that anumber of oxygen sources such as urea, amides (e.g. acetamide,formamide, dimethylacetamide, dimethylformamide) alcohols (e.g.methanol, ethanol, propanol, butanol), water, sulfoxides (e.g. dimethylsulfoxide) and the like would be suitable. Of course, since it is theoxygen functionality of the above that is the "source of oxygen" and notthe length or nature of the side chain, the higher analogs of the aboveshould also be suitable. It has even been found that the anionic portionof the salt can be a suitable oxygen source as illustrated below.

Clearly, water is the preferred reagent since the salts are soluble inthe reaction medium and the product normally precipitates are formed.Since a halogen acid is the expected byproduct, it is especiallypreferred to run the reaction in the presence of a base whichneutralizes the acid formed. Any base capable of neutralizing the acidformed would be suitable. Preferred are the commonly availablecarbonates, bicarbonates, salts of organic acids such as acetates, andhydroxides.

Again, the conversion is very facile. In an especially preferred processthe 2-alkyl-3-haloisothiazolium salt of this invention is added to asodium acetate solution. As the product is formed it normallyprecipitates from the reaction medium and can be collected byfiltration.

Neither temperature nor time appears to be critical, for convenience itis preferred to carry out the reaction at room temperature, but reactiontemperatures from below 0° C. to above 100° C. would be suitable.

The reaction time may vary from a few minutes to 12 hrs and would, ofcourse, be dependent on the temperature.

An alternative method of synthesis is available when the anion is asuitable oxygenated species, e.g. a sulfate derivative such as methylsulfate. In such cases the 2-alkyl-3-haloisothiazolium salt may bepyrolysed to yield the desired 2-alkyl-4-isothiazolin-3-one asillustrated below. The pyrolysis temperature may vary from 150° C. to300° C. with 160° C. to 220° C. being especially preferred. ##STR8##

It should be noted that while ethanol, reacts with the2-alkyl-3-haloisothiazolium salt to convert it to2-alkyl-4-isothiazolin-3-one, ethanol can be used as the solvent whenthe salt is reacted with thiourea to form the corresponding2-alkyl-4-isothiazolin-3-thione. Apparently the thiourea reacts morerapidly than the ethanol.

It is difficult to determine in a reaction with both urea and ethanolpresent, just where the oxygen comes from which forms the carbonyl groupof the 2-alkyl-4-isothiazolin-3-one produced. It is sufficient to notethat the 2-alkyl-3-haloisothiazolium salts of this invention are veryreactive and are capable of reacting with a number of oxygen bearingreagents to form 2-alkyl-4-isothiazolin-3-ones.

As mentioned, the novel 2-alkyl-3-haloisothiazolium salts, I, the novel2-alkyl-4-isothiazolin-3-thiones, III, and2-alkyl-3-dicyanomethylene-4-isothiazolines, IV, are effectiveantibacterial and antifungal agents.

These novel compounds (i.e. I, III and IV) may be added to such aqueoussystems or formulations that are susceptible to bacterial or fungalgrowth, either undiluted or dissolved in organic solvents such asalcohols, acetone, dimethylformamide and the like. They may be addedalone or in combination with other biocides and/or functional compoundssuch as antioxidants, anticorrosive agents, surfactants, etc.

Concentrations from about 0.001% to above 1.0% are effective. Use oflarger concentrations, while feasible, is recommended only for unusualapplications. It is preferred to use concentrations from about 0.005% toabout 0.5%.

The novel compounds I, III and IV may also be used as preservatives foroil in water emulsions. A number of oil in water emulsions are used inindustry, for example in the high speed metal working and textileindustries, for their cooling, lubricating, antistatic and anticorrosiveproperties. Unless adequately protected by an effective preservative,such systems are susceptible to bacterial decomposition producingobnoxious odors and potential health hazards. [Detailed descriptions ofthese systems, their microbiological problems and difficulties in theirpreservation can be found in: Bennet, E. O. Soap Chem. Specialties, 32,46 (1956). Fabian, F. W. & Pivnick, H., Applied Microbiology, 1,(1953).]

In practicing the invention, the compound may be added by directlydissolving it in the concentrated oil which is then diluted with waterto form the water oil emulsion, or it may be added to the final emulsioneither undiluted or dissolved in a solvent such as dimethylformamide,alcohol, acetone, etc. Similar methods known in the art for addingpreservatives to such water and oil emulsions may also be used.

There can be used as little as about 0.005%. Although amounts greaterthan 0.3% are operable, they are recommended only for unusualapplications. It is preferred to use amounts in the range of from about0.01% to about 0.20%, with amounts in the range of about 0.02% to 0.10%being especially preferred.

The novel compounds I, III and IV may also be used as cosmeticpreservatives [Problems encountered in the preservation of cosmetics aredescribed by Dunnigan, A.P., Drug and Cosmetic Industries, 103, 43,(1968)].

The compounds may be added to the finished cosmetic product directly ordissolved in suitable solvents such as alcohol, acetone, dimethylformamide and the like. Alternatively the compounds may be dissolved inthe oils or other raw materials used in the formula and then formulatedin the final product.

In cosmetic preparations, concentrations as low as 0.01% are found to beoperable. Concentrations greater than 0.30%, while operable, arerecommended only for unusual applications. Concentrations in the rangeof from about 0.02% to about 0.20% are preferred with concentrations ofabout 0.05% to 0.10% being especially preferred.

The novel compounds I, III and IV are particularly effective asslimicides. For example they can be used to protect so-called whitewater systems utilized in paper manufacture from the formation of slimesand the like which are known to affect these systems. Concentrations aslow as 0.001% are found to be operable. Concentrations greater than0.20%, while operable, are recommended only for unusual applications.Concentrations in the range of from about 0.002% to about 0.1% arepreferred with concentrations of about 0.005 to about 0.01% beingespecially preferred.

While the compound is effective when added directly, it is preferred toadd it dissolved in a suitable solvent such as diethylene glycol,dipropylene glycol or polyethylene glycol and the like. Other methodsknown in the art for adding preservatives to such aqueous systems mayalso be used.

The novel compounds I, III and IV are also effective preservatives oflatex paints. They may be incorporated into the paint in a variety ofways. It is expected that those skilled in the art would determine thepreferred method of introducing it in the paint. Among the methodsavailable are introducing the fungicide as the paint is blended, mullingthe fungicide into the paint, introducing a solution of the fungicideinto the paint etc.

Normally the concentration of the compounds in the paint will be lessthan 1.0% Higher amounts, though operable, would not be economical.

An amount of the novel compound at a concentration level of 0.1% to 1.0%in the liquid paint would suffice for most purposes. A concentration ofabout 0.2% to 0.7% is preferred for most applications, with about 0.5%being especially preferred.

ILLUSTRATION OF PREFERRED EMBODIMENTS

A number of examples are provided herein to illustrate the preferredembodiments of this invention. Included are examples directed to thesynthesis of the novel compounds of this invention and examples directedto the utility of these compounds.

The examples provided herein are included for the sole purpose ofillustrating the preferred embodiments and should not be construed aslimiting. They are intended to embrace any equivalents or obviousextensions which are known or should be known to a person skilled in theart.

Synthesis of the 2-Alkyl-3-haloisothiazolium Salts

The following examples illustrate the method of synthesis of the2-alkyl-3-haloisothiazolium salts of this invention.

EXAMPLE I A. 2-Methyl-3,4,5-trichloroisothiazolium fluorosulfonate

Trichloroisothiazole (37.7 g, 0.20 mol) and 38 ml of methylfluorosulfonate were mixed under a nitrogen atmosphere. The mixture washeated at 70°-80° for 30 min. The resulting solid was washed with etherand benzene to yield 55.6 g (96%) of2-methyl-3,4,5-trichloroisothiazolium fluorosulfonate, mp 162 (d).Analysis calculated for C₄ H₃ Cl₃ FNO₃ S₂ : C, 15.87; H, 0.99; N, 4.63;Found: C, 15.81; H, 1.02; N, 4.49.

B. 2-Methyl-3,4,5-trichloroisothiazolium methylsulfate

Trichloroisothiazole (37.7 g, 0.20 mol) and dimethyl sulfate (9.5 ml,0.1 mol) were mixed under a nitrogen atmosphere. The mixture was heatedat 135°-140° for 1 hr. The reaction mixture was cooled and poured into100 ml of ether. The resulting solid was collected and washed with warmglyme to yield 14.5 g, (46%), mp 130°. The NMR and IR were consistentwith the assigned structure.

C. 2-Methyl-3,4,5-trichloroisothiazolium hexafluorophosphate

Trichloroisothiazole (15 ml) and 6.2 g (0.03 mol) of trimethyloxomiumhexafluorophosphate were heated at 90° for 1 hr under nitrogen. Aftercooling, ether (100 ml) was added and the solid collected to yield 6.3 g(61%) of product, mp >240. Spectral data (NMR & IR) were consistent withthe assigned structure.

D. 2-Methyl-3,4,5-trichloroisothiazolium trifluoromethane sulfonate

Trichloroisothiazole (9.4 g, 0.05 mol) and 9 ml of methyltrifluoromethane sulfonate were heated at 65° for 30 min. After cooling,ether (150 ml) was added and the solid collected to yield 4.6 g (26%) ofproduct, mp 118-120. Spectral data (NMR & IR) were consistent with theassigned structure.

E. 2-Methyl-3,4,5-trichloroisothiazolium hexachloroantimonate

Trichloroisothiazole (10 ml) and trimethyloxonium hexachloroantimonate(7.9 g, 0.02 mol) were heated at 90° for 30 min. After cooling ether(150 ml) was added and the solid collected to yield 7.8 g (73%) ofproduct, mp >240. Spectral data (NMR & IR) were consistent with theassigned structure.

F. 2-Methyl-3,4,5-tribromoisothiazolium fluorosulfonate

Tribromoisothiazole (2.2 g, 0.007 mol) and 2.2 ml of methylfluorosulfonate were heated at 65° for 10 min. under a nitrogenatmosphere. The resulting solid was washed with ether and benzene toyield 2.7 g. (88%) of 2-methyl-3,4,5-tribromoisothiazoliumfluorosulfonate, mp 121-129. Spectral data (NMR and IR) were consistentwith the assigned structure.

G. 3,4-Dichloro-2,5-dimethylisothiazolium fluorosulfonate

3,4-Dichloro-4-methylisothiazole (6.5 g, 0.039 mol) and 7 ml of methylfluorosulfonate were heated at 70° for 30 min. under a nitrogenatmosphere. The resulting solid was washed with ether and benzene toyield 10.1 g (92%) of 3,4-dichloro-2,5-dimethylisothiazoliumfluorosulfonate, mp 152-162. Analysis calculated for C₅ H₆ Cl₂ FNO₃ S₂ :C, 21.28; H, 2.14; Cl, 25.13; N, 4.97; S, 22.73. Found: C, 21.22; H,2.19; Cl, 25.01; N, 5.18; S, 22.74.

H. 4-Cyano-3,5-dichloro-2-methylisothiazolium fluorosulfonate

4-Cyano-3,5-dichloroisothiazole (5.0 g, 0.028 mol) and 4 ml of methylfluorosulfonate were heated at 80°-90° for 30 min under a nitrogenatmosphere. The resulting solid was washed with ether and benzene toyield 7.5 g (92%) of 4-cyano-3,5-dichloro-2-methylisothiazoliumfluorosulfonate, mp 160-170. Spectral data (NMR and IR) were consistentwith the assigned structure. Analysis calculated for C₅ H₃ Cl₂ FN₂ O₃ S₂: C, 20.50; H, 1.02; Found: C, 20.27; H, 1.44.

I. 5-Cyano-3,4-dichloro-2-methylisothiazolium fluorosulfonate

5-Cyano-3,4-dichloroisothiazole (3.6 g, 0.02 mol) and 4 ml of methylfluorosulfonate were heated at 80°-100° for 11/2 hrs under a nitrogenatmosphere. The resulting solid was washed with ether and benzene toyield 4.5 g (77%) of 5-cyano-3,4-dichloro-2-methyl isothiazoliumfluorosulfonate, mp 163-174 (d). Spectral data (NMR and IR) wereconsistent with the assigned structure.

J. 3,4-Dichloro-2-methyl-5-ethoxycarbonylisothiazolium fluorosulfonate

3,4-Dichloro-5-ethoxycarbonylisothiazole (6.0 g, 0.027 mol) and 4 ml ofmethyl fluorosulfonate were heated at 110° for 1 hr under a nitrogenatmosphere. The solid was washed with ether and benzene to yield 9.0 g(99%) of 3,4-dichloro-2-methyl-5-ethoxycarbonylisothiazoliumfluorosulfonate, mp 118-123. Analysis calculated for C₇ H₈ Cl₂ FNO₅ S₂ :Cl, 20.84; N, 4.12; S, 18.85. Found Cl, 20.56; N, 4.06; S, 18.89.

K. 3,4-Dichloro-2-methylisothiazolium fluorosulfonate

3,4-Dichloroisothiazole (3.1 g, 0.02 mol) and 4 ml of methylfluorosulfonate were heated at 40° for 15 min under a nitrogenatmosphere. The resulting solid was washed with ether and benzene toyield 3.4 g (63%) of 3,4-dichloro-2-methylisothiazolium fluorosulfonate,mp 159-164. Analysis calculated for C₄ H₄ Cl₂ FNO₃ S₂ : C, 17.90; H,1.49; Cl, 26.45; F, 7.90; N, 5.22. Found C, 17.74; H, 1.49; Cl, 26.49;F, 7.24; N, 5.13.

L. 2-Propyl-3,4,5-trichloroisothiazolium trifluoromethane sulfonate

Trichloroisothiazole (4.7 g, 0.025 mol) and a solution of 0.02 mol ofn-propyl trifluoromethane sulfonate in CCl₄ were heated at 110° and CCl₄was removed via distillation. After heating at 110° for 11/2 hrs, thereaction was cooled and ether added. The ether was cooled in an ice bathand the solid collected to yield 2.1 g (28%) of product, mp 95°-99°.Analysis calculated for C₇ H₇ Cl₃ F₃ NO₃ S: C, 22.09; H, 1.86; Cl,27.95; N, 3.68; S, 16.84. Found: C, 2160; H, 1.94; Cl, 27.15; N, 3.57;S, 16.27.

M. 2-Octyl-3,4,5-trichloroisothiazolium trifluoromethane sulfonate

Trichloroisothiazole (6.6 g, 0.035 mol) and n-octyl trifluoromethanesulfonate (7.5 g, 0.0286 ml) were heated at 110° for 2 hrs. Aftercooling, 150 ml of ether was added and solution cooled in a dryice/acetone bath. The ether was decanted and the brown oil dried toyield 4.0 g (31%) of product. Spectral data (NMR & IR) were consistentwith the assigned structure.

N. 2-(2-Propen-1-yl)-3,4,5-trichloroisothiazolium trifluoromethanesulfonate

Trichloroisothiazole (5.7 g, 0.03 ml) and a solution of allyltrifluoromethane sulfonate (0.03 mol) in CCl₄ were heated and excessCCl₄ was removed by distillation until the reacting temperature reached90° C. After heating at 90° for 30 min, the reaction was cooled and 150ml of ether added. The solid was collected to yield 2.6 g (30%) ofproduct, mp 103-105. Spectral data (NMR & IR) were consistent with theassigned structure.

O. 2-Ethyl-3,4,5-trichloroisothiazolium tetrafluoroborate

Trichloroisothiazole (37.7 g, 0.20 mol) and triethyloxonium fluoroborate(19.0 g, 0.10 mol) were heated at 110° for 1 hr under a nitrogenatmosphere. The resulting solid was washed with ether to yield 15.1 g(50%) of 2-ethyl-3,4,5-trichloroisothiazolium, tetrafluoroborate mp193-197. Analysis calculated for C₅ H₅ BCl₃ F₄ NS: C, 19.74; H, 1.64;Cl, 34.95; N, 4.59; S, 1054. Found: C, 19.88; H, 1.70; Cl, 35.05; N,4.58; S, 10.91.

P. 2-Methyl-3-chloroisothiazolium nitrate

3-Chloroisothiazolium fluorosulfonate (6.9, 0.03) and 5.1 g of AgNO₃were dissolved in 280 ml of acetonitrile. After stirring for 30 min, theAgOSO₂ F was removed by filtration and the acetonitrile concentrated onthe rotary evaporator. THF was added and the solid collected to yield5.8 g (98%) of product, mp 175 (d). Spectral data (NMR & IR) wereconsistent with assigned structure.

Q. Other 2-alkyl-3-haloisothiazolium salts

A number of other 2-alkyl-3-haloisothiazolium salts were prepared in asimilar manner and are listed in Table I, Example II.

Illustration of General Antimicrobial Activity EXAMPLE II2-Alkyl-3-chloroisothiazolium salts

Antibacterial and antifungal activity were evaluated by a 5-fold serialdilution test in agar. In this test, compounds were prepared as 6%solutions in dimethylformamide or ethanol. The 6% solution was then5-fold serially diluted in test tubes to give the desired concentrationswhen mixed with agar and poured into sterile Petri dishes. Tryptoneglucose extract agar was used for the bacterial testing; mildew glucoseagar for the fungal testing. The bacterial plates were spot inoculatedwith 24-hour nutrient broth cultures and incubated at 37° C. for 48hours. The fungal plates were spot inoculated with spore suspensions andincubated at 28° C. for seven days. At the end of the incubationperiods, all plates were examined for growth. The minimum inhibitoryconcentration (MIC) for each organism is expressed in Table I. In theranges presented, growth is observed only in the lower concentration.The key to Table I is as follows:

    ______________________________________                                        Activity    Growth @    No Growth @                                           ______________________________________                                        0           >1920   μg/ml                                                  1           384     μg/ml                                                                              1920    μg/ml                                  2           76      μg/ml                                                                              384     μg/ml                                  3           15      μg/ml                                                                              76      μg/ml                                  4           3       μg/ml                                                                              15      μg/ml                                  5           0.6     μg/ml                                                                              3       μg/ml                                  6           0.12    μg/ml                                                                              0.6     μg/ml                                  7           .03     μg/ml                                                                              .12     μg/ml                                  8                           <.03    μg/ml                                  ______________________________________                                    

The organisms tested are:

    ______________________________________                                               Bacteria       Fungi                                                   ______________________________________                                        B.sub.1  S. aureus      F.sub.1                                                                              A. niger                                       B.sub.2  E. coli        F.sub.2                                                                              A. oryzae                                      B.sub.3  P. aeruginosa  F.sub.3                                                                              P. piscarium                                   B.sub.4  P. vulgaris    F.sub.4                                                                              A. pullulans                                   B.sub.5  B. subtilis                                                          ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________     ##STR9##                                                                                             Melting                                                                            Minimum Inhibitory Concentration Range           Cation            Anion Point                                                                              Bacteria    Fungi                                No.                                                                              R   X Y   Z    A.sup.-                                                                             °C.                                                                         B.sub.1                                                                          B.sub.2                                                                         B.sub.3                                                                         B.sub.4                                                                         B.sub.5                                                                          F.sub.1                                                                         F.sub.2                                                                         F.sub.3                                                                         F.sub.4                        __________________________________________________________________________     1 CH.sub.3                                                                          Cl                                                                              Cl  Cl   .sup.- O.sub.3 SF                                                                   162 (d)                                                                            6  6 5 6 6  8 8 8 8                               2 CH.sub.3                                                                          Cl                                                                              Cl  Cl   .sup.- O.sub.3 SOMe                                                                 135-140                                                                            5  5 4 5 5  8 8 8 8                               3 CH.sub.3                                                                          Cl                                                                              Cl  Cl   .sup.- SbCl.sub.6                                                                   >240 4  5 4 5 5  6 6 7 7                               4 CH.sub.3                                                                          Cl                                                                              Cl  Cl   .sup.- O.sub.3 SCF.sub.3                                                            118-20                                                                             5  5 4 5 5  7 7 7 8                               5 CH.sub.3                                                                          Cl                                                                              Cl  Cl   .sup.- PF.sub.6                                                                     >240 4  3 3 4 5  6 6 5 7                               6 CH.sub.3                                                                          Br                                                                              Br  Br   .sup.- O.sub.3 SF                                                                   121-9 (d)                                                                          4  3 3 4 5  6 6 5 7                               7 Ethyl                                                                             Cl                                                                              Cl  Cl   .sup.- BF.sub.4                                                                     193-7                                                                              6  5 3 6 6  8 8 8 8                               8 Ethyl                                                                             Cl                                                                              Cl  Cl   .sup.- O.sub.3 SF                                                                   124-7                                                  9 Ethyl                                                                             Cl                                                                              Cl  Cl   .sup.- O.sub.3 SOEt                                                                 liquid                                                10 Propyl                                                                            Cl                                                                              Cl  Cl   .sup.- O.sub.3 SCF.sub.3                                                             95-9                                                                              5  5 3 5 5  7 7 7 7                              11 Allyl                                                                             Cl                                                                              Cl  Cl   .sup.- O.sub.3 SCF.sub.3                                                            103-5                                                                              4  4 3 4 4  7 7 8 7                              12 Octyl                                                                             Cl                                                                              Cl  Cl   .sup.- O.sub.3 SCF.sub.3                                                            liquid                                                                             4  4 3 4 5  8 7 7 7                              13 CH.sub.3                                                                          Cl                                                                              H   H    .sup.- O.sub.3 SF                                                                   215-26                                                                             2  3 3 4 4  2 2 3 3                              14 CH.sub.3                                                                          Cl                                                                              H   H    .sup.- O.sub.3 SOMe                                                                 100-3                                                                              2  3 3 3 3  3 1 2 2                              15 CH.sub.3                                                                          Cl                                                                              H   H    .sup.- NO.sub.3                                                                     175 (d)                                                                            3  3 3 3 3  4 4 5 3                              16 CH.sub.3                                                                          Cl                                                                              H   H    .sup.- SbCl.sub.6                                                                   >240 2  2 3 3 3  3 3 3 3                              17 CH.sub.3                                                                          Cl                                                                              H   H    .sup.- PF.sub.6                                                                     >240 2  3 3 3 3  1 1 2 2                              18 Ethyl                                                                             Cl                                                                              H   H    .sup.- O.sub.3 SOEt                                                                 liquid                                                                             2  3 2 3 2  1 1 2 2                              19 Ethyl                                                                             Cl                                                                              H   H    .sup.- O.sub.3 SF                                                                    81-3                                                                              2  3 3 3 3  3 3 3 4                              20 Propyl                                                                            Cl                                                                              H   H    .sup.- O.sub.3 SCF.sub.3                                                             50-3                                                                              2  3 2 3 3  3 2 3 3                              21 Octyl                                                                             Cl                                                                              H   H    .sup.- O.sub.3 SCF.sub.3                                                            liquid                                                                             3  3 1 3 4  5 5 5 6                              22 CH.sub.3                                                                          Cl                                                                              Cl  H    .sup.- O.sub.3 SF                                                                   159-64                                                                             4  4 3 4 4  1 2 2 2                              23 CH.sub.3                                                                          Cl                                                                              Cl  H    .sup.- O.sub.3 SOMe                                                                  81-85                                                                             4  4 3 5 5  2 2 2 2                              24 CH.sub.3                                                                          Cl                                                                              Cl  COOEt                                                                              .sup.- O.sub.3 SF                                                                   107-110                                                                            3  3 2 4 4  2 2 2 2                              25 CH.sub.3                                                                          Cl                                                                              Cl  CN   .sup.- O.sub.3 SF                                                                   167-74                                                                             3  3 2 4 4  3 2 2 2                              26 CH.sub.3                                                                          Cl                                                                              CN  Cl   .sup.- O.sub.3 SF                                                                   160 (d)                                                                            4  4 3 4 4  4 4 4 5                              27 CH.sub.3                                                                          Cl                                                                              Cl  CH.sub.3                                                                           .sup.- O.sub.3 SF                                                                   155  2  2 1 2 2  3 3 3 3                              28 CH.sub.3                                                                          Cl                                                                              NO.sub.2                                                                          H    .sup.- O.sub.3 SF                                                                   145-150                                                                            1  1 1 2 2  1 1 2 3                              __________________________________________________________________________

Illustration of Specific Applications EXAMPLE III

The efficacy of 2-alkyl-3-haloisothiazolium salts as a preservative forcutting oil emulsions was demonstrated by the following test:

Various aliquots of a 6% solution of the chemical in ethanol were addedto cutting oil emulsions prepared by diluting Kutwell 30 cutting oilconcentrate 1 to 30 with water. These samples were inoculated with aculture of Ps. aeruginosa and incubated at 28° on a rotary shaker. Atweekly intervals the samples were examined for microorganisms and thenreinoculated and incubated. Results are tabulated in Table II.

                                      TABLE II                                    __________________________________________________________________________     ##STR10##                                                                    MINIMUM INHIBITORY CONCENTRATION (μg/ml)                                   Cation             Anion  Incubation Period (Weeks)                           R    X  Y    Z     A.sup.-                                                                              1  2   3   4                                        __________________________________________________________________________    CH.sub.3                                                                           Cl Cl   Cl    .sup.- O.sub.3 SF                                                                    <16                                                                              <16 <16 <16                                      CH.sub.3                                                                           Cl Cl   Cl    .sup.- O.sub.3 SOMe                                                                  <2 <2  <16 <16                                      CH.sub.3                                                                           Cl Cl   Cl    .sup.- SbCl.sub.6                                                                    2  2   2   64                                       CH.sub.3                                                                           Cl Cl   Cl    .sup.- O.sub.3 SCF.sub.3                                                             2  2   16  64                                       Ethyl                                                                              Cl Cl   Cl    .sup.- BF.sub.4                                                                      4  8   8   32                                       Propyl                                                                             Cl Cl   Cl    .sup.- O.sub.3 SCF.sub.3                                                             <32                                                                              <32 <32 <32                                      CH.sub.3                                                                           Cl H    H     .sup.- O.sub.3 SF                                                                    32 32  32  32                                       CH.sub.3                                                                           Cl H    H     .sup.- O.sub.3 SOMe                                                                  64 64  64  64                                       CH.sub.3                                                                           Cl H    H     .sup.- NO.sub.3                                                                      8  8   8   8                                        CH.sub.3                                                                           Cl H    H     .sup.- SbCl.sub.6                                                                    8  16  16  16                                       CH.sub.3                                                                           Cl H    H     .sup.- PF.sub.6                                                                      32 32  32  32                                       Ethyl                                                                              Cl H    H     .sup.- O.sub.3 SOEt                                                                  125                                                                              125 125 500                                      Propyl                                                                             Cl H    H     .sup.- O.sub.3 SCF.sub.3                                                             125                                                                              250 250 500                                      CH.sub.3                                                                           Cl Cl   H     .sup.- O.sub.3 SF                                                                    32 32  125 250                                      CH.sub.3                                                                           Cl Cl   H     .sup.- O.sub.3 SOMe                                                                  32 32  32  32                                       CH.sub.3                                                                           Cl Cl   COOEt .sup.- SF                                                                            125                                                                              250 250 250                                      CH.sub.3                                                                           Cl Cl   CN    .sup.- O.sub.3 SF                                                                    <16                                                                              125 250 250                                      CH.sub.3                                                                           Cl CN   Cl    .sup.- O.sub.3 SF                                                                    <16                                                                              125 250 250                                      CH.sub.3                                                                           Cl Cl   CH.sub.3                                                                            .sup.- O.sub.3 SF                                                                    125                                                                              250 500 500                                      CH.sub.3                                                                           Cl NO.sub.2                                                                           H     .sup.- O.sub.3 SF                                                                    125                                                                              500 500 500                                      __________________________________________________________________________

EXAMPLE IV

The efficacy of 2-alkyl-3-haloisothiazolium salts as a preservative forlatex paints was demonstrated by the following test.

Various quantities of the chemical were incorporated into a whiteexterior vinyl acetate paint. Whatman #30 filter paper was painted withone coat of paint on each side. One inch squares were cut and placed inPetri dishes on a malt agar.

The surface of both the agar and the painted squares were inoculatedwith a spore suspension of Aureobasidium pullulans. The plates wereexamined for zones of inhibition and surface growth after three weeksincubation in a humidity chamber at 27°-28°. The results are tabulatedin Table III.

                                      TABLE III                                   __________________________________________________________________________     ##STR11##                                                                                         Conc. 0.5% Conc. 0.25%                                                        A. pullulans                                                                             A. pullulans                                  R   X  Y   Z  A.sup.-                                                                              Zone Surface                                                                             Zone Surface                                  __________________________________________________________________________    CH.sub.3                                                                          Cl Cl  Cl .sup.- O.sub.3 SF                                                                    >20.sup.a                                                                          None.sup.b                                                                          0    None                                     CH.sub.3                                                                          Cl Cl  Cl .sup.- O.sub.3 SOMe                                                                  >20  None  0    None                                     CH.sub.3                                                                          Cl CN  Cl .sup.- O.sub.3 SF                                                                     0   None  0    None                                     CH.sub.3                                                                          Cl Cl  H  .sup.- O.sub.3 SF                                                                     0   None  0    None                                     Et  Cl Cl  Cl .sup.- O.sub.3 SCF.sub.3                                                             20   None  20   None                                     CH.sub.3                                                                          Cl Cl  Cl .sup.- SbCl.sub.6                                                                    20   None  20   None                                     Control               0   Heavy 0     Heavy                                   __________________________________________________________________________     .sup.a Zone sizes are in mm.                                                  .sup.b Growth on the surface on painted square: none, medium or heavy.   

EXAMPLE V

The utility of the isothiazolium salts as a slimicide for pulp and papermill water systems was demonstrated by the following study using2-methyl-3,4,5-trichloroisothiazolium methyl sulfate.

Various quantities of a 6% solution of this compound indimethylformamide were incorporated into 24 ml of a test substratecomposed as follows:

8.4 g Whatman No. 2 cellulose

2.6 g Sodium nitrate

1.0 g Calcium sulfate

6.5 g Maltose

1.0 g Nutrient Broth, Difco

10.0 ml Mersize Rm 70R (Monsanto)

2.5 ml 2% Alum

990 ml Distilled Water

The samples were inoculated with four different organisms and incubatedat 28° C. At weekly intervals the samples were examined for the presenceof microbial growth and reinoculated during a total incubation period offour weeks. The results as tabulated in Table IV show that2-methyl-3,4,5-trichloroisothiazolium methyl sulfate is effective as aslimicide at a conentration of <0.01%.

                  TABLE IV                                                        ______________________________________                                        Effectiveness of 2-Methyl-3,4,5-Trichloroisothiazolium Methyl                 Sulfate As a Slimicide (mcg/ml)                                                       Minimum inhibitory concentration (μg/ml)                                   Weeks                                                                 Organism  1        2          3      4                                        ______________________________________                                        P. aeruginosa                                                                           7.8      7.8        7.8    7.8                                      E. aerogenes                                                                            3.9      3.9        3.9    3.9                                      A. niger  3.9      3.9        3.9    3.9                                      P. Piscarium                                                                            3.9      3.9        3.9    3.9                                      ______________________________________                                    

Synthesis of 2-Alkyl-3-dicyanomethylene-4-isothiazolines EXAMPLE VI4-Chloro-3-dicyanomethylene-5-ethoxycarbonyl-2-methyl-4-isothiazoline

3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (7.5g, 0.022 mole) was dissolved in 75 ml of isopropanol. Malononitrile (1.5g, 0.023 mol) was added the mixture stirred for 30 min. The yellow solidwas collected and washed with isopropanol to yield 2.6 g (44%) ofproduct, mp 134-136. Analysis calculated for C₁₀ H₈ ClN₃ O₂ S₂ : C44.51; H, 3.00; Cl, 13.16; N, 15.57; S, 11,90. Found: C, 44.34; H, 2.82;Cl, 12.60; N, 14.82; S, 11.42.

The other 2-alkyl-3-dicyanomethylene-4-isothiazolines can be prepared ina similar manner. A number of these are listed in Table V, Example VII.

Illustration of the General Antimicrobial Activity of the2-Alkyl-3-dicyanomethylene-4-isothiazolines EXAMPLE VII

The 2-alkyl-3-dicyanomethylene-4-isothiazolines were tested forantimicrobial activity as described in Example II. The results arelisted in Table V. The key to the activity levels and the microorganismsused is as described in Example II.

                                      TABLE V                                     __________________________________________________________________________     ##STR12##      Melting                                                                             Bacteria       Fungi                                    R     Y  Z     Point B.sub.1                                                                          B.sub.2                                                                          B.sub.3                                                                          B.sub.4                                                                          B.sub.5                                                                          F.sub.1                                                                          F.sub.2                                                                          F.sub.3                                                                          F.sub.4                          __________________________________________________________________________    CH.sub.3                                                                            Cl Cl    251 (d)                                                                             4  3  2  3     4  4  4  5                                CH.sub.2 CH.sub.3                                                                   Cl Cl    170-171                                                                             4  4  3  4  4  4  4  4  4                                CH.sub.3                                                                            H  H     235-237                                                                             2  3  1  4  3  1  0  1  1                                CH.sub.2 CH.sub.3                                                                   H  H     57-59 3  3  2  4  4  1  1  1  2                                CH.sub.3                                                                            Cl H     135 (d)                                                                             3  4  3  4  4  1  1  1  2                                CH.sub.3                                                                            Cl COOEt 134-136                                                                             2  2  1  2  3  1  1  1  1                                CH.sub.3                                                                            Cl CN    190 (d)                                                                             3  2  0  3  3  2  1  2  3                                CH.sub.3                                                                            Cl CH.sub.3                                                                            224-226                                                                             3  3  0  5  5  0  0  0  1                                __________________________________________________________________________

EXAMPLE VIII

The efficacy of 2-alkyl-3-dicyanomethylene-4-isothiazolines as apreservative for cutting oil emulsions was demonstrated by the test ofExample III. Results are tabulated in Table VI.

                  TABLE VI                                                        ______________________________________                                         ##STR13##        Incubation Period (weeks)Concentration                                       (μg/ml)Minimum Inhibitory                                 R       Y      Z         1     2     3     4                                  ______________________________________                                        CH.sub.3                                                                              Cl     Cl        125   125   250   250                                C.sub.2 H.sub.5                                                                       H      H         125   250   250   500                                CH.sub.3                                                                              Cl     COOEt     125   125   125   125                                CH.sub.3                                                                              Cl     CN        62    250   250   250                                CH.sub.3                                                                              H      H         250   500   500   500                                CH.sub.3                                                                              Cl     CH.sub.3  250   500   500   1000                               CH.sub.3                                                                              Cl     H         <32   <32   <32   <32                                ______________________________________                                    

EXAMPLE IX

The test of Example V was used to determine the effectiveness of4,5-dichloro-3-dicyanomethylene-2-methyl-4-isothiazoline as a slimicide.The results are tabulated in Table VII.

                  TABLE VII                                                       ______________________________________                                                   Minimum Inhibitory                                                            Concentration (μg/ml)                                                      Weeks                                                              Organism     1      2          3    4                                         ______________________________________                                        P. aeruginosa                                                                              250    250        250  250                                       E. aerogenes 250    250        250  250                                       A. niger     250    500        500  500                                       P. Piscarium 250    250        250  500                                       ______________________________________                                    

Synthesis of 2-Alkyl-4-isothiazolin-3-thiones EXAMPLE X A.4,5-Dichloro-2-methyl-4-isothiazolin-3-thione

2-Methyl-3,4,5-trichloroisothiazolium methylsulfate (10.7 g) thiourea(2.6 g) were added to 100 ml of ethanol at room temperature. Afterstirring overnight the product which had precipitated from solution wascollected by filtration and recrystallized from ethanol to yield 5.3 g(78%) of 4,5-dichloro-2-methyl-4-isothiazolin-3-thione, mp 143-144.Analysis: Calculated for C₄ H₃ ClNS₂ : C, 24.00; H, 1.50; N, 7.00; Cl,35.45; S, 32.05. Found: C, 24.07; H, 1.45; N, 7.00; Cl, 35.67; S, 31.78.

Other 2-alkyl-4-isothiazolin-3-thiones can be prepared in a similarmanner. A number of these are listed in Table VIII, Example XI.

EXAMPLE XI

The 2-alkyl-4-isothiazolin-3-thiones were tested for antimicrobialactivity as described in Example II. The results are listed in TableVIII. The key to the activity levels and the microorganisms used is asdescribed in Example II.

                                      TABLE VIII                                  __________________________________________________________________________     ##STR14##     Melting                                                                             Bacteria  Fungi                                          No.                                                                             R    Y Z    Point B.sub.1                                                                         B.sub.2                                                                         B.sub.3                                                                         B.sub.4                                                                         B.sub.5                                                                         F.sub.1                                                                         F.sub.2                                                                         F.sub.3                                                                         F.sub.4                                   __________________________________________________________________________    1 CH.sub.3                                                                           Cl                                                                              Cl   143-144                                                                             6 5 4 5   6 6 6 6                                         2 CH.sub.2 CH.sub.3                                                                  Cl                                                                              Cl    99-100                                                                             4 4 3 5 6 6 6 6 7                                         3 CH.sub.3                                                                           H H     99-102                                                                             2 3 2 4 3 2 2 2 3                                         4 CH.sub.3                                                                           Cl                                                                              H    142 (d)                                                                             3 4 2 4 4 4 3 6 5                                         5 CH.sub.3                                                                           Cl                                                                              COOEt                                                                              108-110                                                                             1 2 1 1 1 1 1 1 1                                         6 CH.sub.3                                                                           Cl                                                                              CN   211 (d)                                                                             2 2 1 3 4 1 2 2 4                                         7 CH.sub.3                                                                           Cl                                                                              CH.sub.3                                                                           125-127                                                                             0 1 0 1 1 2 1 2 3                                         __________________________________________________________________________

EXAMPLE XII

The efficacy of 2-alkyl-4-isothiazolin-3-thiones as a preservative forcutting oil emulsions was demonstrated by the test of Example III. Theresults are tabulated in Table IX.

                  TABLE IX                                                        ______________________________________                                         ##STR15##       Incubation Period (weeks)Concentration (μg/ml)Minimum                     Inhibitory                                                    R       Y      Z        1     2     3     4                                   ______________________________________                                        CH.sub.3                                                                              Cl     Cl       <16   62    62    62                                  C.sub.2 H.sub.5                                                                       Cl     Cl       16    32    62    62                                  CH.sub.3                                                                              H      H        125   250   250   250                                 CH.sub.3                                                                              Cl     H        <32   62    62    62                                  CH.sub.3                                                                              Cl     COOEt    250   125   125   62                                  CH.sub.3                                                                              Cl     CN       16    125   250   250                                 ______________________________________                                    

EXAMPLE XIII

Various quantities of 4,5-dichloro-2-methyl-4-isothiazolin-3-thione wereincorporated into a white exterior vinyl acetate paint and tested asdescribed in Example IV.

At both 0.5% and 0.25% the inhibiting zone was 20 mm and there was nogrowth on the surface.

EXAMPLE XIV

The utility of 2-alkyl-4-isothiazolin-3-thiones as a slimicide wastested as in Example V. The results are presented in Table X.

                  TABLE X                                                         ______________________________________                                        Effectiveness of 4,5-dichloro-2-methyl-4-isothiazolin-3-thione as a           slimicide (mcg/ml).                                                                      Minimum Inhibitory                                                            Concentration (μg/ml)                                                      Weeks                                                              Organism     1      2          3    4                                         ______________________________________                                        P. aeruginosa                                                                               16     16         16   16                                       E. aerogenes <8     <8          16   16                                       A. niger     <8     <8         <8   <8                                        P. piscarium <8     <8         <8    16                                       ______________________________________                                    

Synthesis of 2-Alkyl-4-isothiazolin-3-ones From the Corresponding2-Alkyl-3-halo-isothiazolium Salts

The following examples illustrate the conversion of the2-alkyl-3-halo-isothiazolium salts of this invention to theantimicrobially active 2-alkyl-4-isothiazolin-3-ones.

EXAMPLE XV 4,5-Dichloro-2-methyl-4-isothiazolin-3-one

2-Methyl-3,4,5-trichloroisothiazolium methylsulfate (15.5 g, 0.05 ml)was heated at 180°-190° until gas evolution ceased. The solid wasrecrystallized from chloroform to yield 4.6 g (50%) of4,5-dichloro-2-methyl-4-isothiazolin-3-one, mp 117-120.

This example illustrates the method by which a2-alkyl-3-halo-isothiazolium salt having a suitably oxygenated anion canbe converted to the corresponding 2-alkyl-4-isothiazolin-3-one bypyrolysis.

EXAMPLE XVI

This example illustrates how the 2-alkyl-4-isothiazolin-3-ones can beprepared by reacting the corresponding 2-alkyl-3-haloisothiazolium saltwith aqueous base.

A. 4,5-Dichloro-2-methyl-4-isothiazolin-3-one

2-Methyl-3,4,5-trichloroisothiazolium fluorosulfonate (16.9 g, 0.058mol) was added in portions to 150 ml of a saturated sodium acetatesolution. After stirring for 30 min. the solid was collected, washedwith water, and recrystallized from ethanol to yield 7.5 g (70%) of4,5-dichloro-2-methyl-4-isothiazolin-3-one, mp 119°-120°.

B. 4-Chloro-2-methyl-4-isothiazolin-3-one

3,4-Dichloro-2-methylisothiazolium fluorosulfonate (13.1 g, 0.049 mol)was added in portions to 150 ml of a saturated sodium acetate solution.After stirring for 30 min., the solid was collected and recrystallizedfrom heptane to yield 5.2 g (70%) of4-chloro-2-methyl-4-isothiazolin-3-one, mp 87°-90°. Analysis: Calculatedfor C₄ H₄ ClNOS: C, 32.09; H, 2.67; Cl, 23.73; N, 9.36; S, 21.46. Found:C, 32.30; H, 2.72; Cl, 23.74; N, 9.11; S, 21.72.

C. 4-Chloro-5-ethoxycarbonyl-2-methyl-4-isothiazolin-3-one

3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (4.2g, 0.012 mol) was added to 50 ml of saturated K₂ CO₃ solution. Theaqueous phase was extracted wih 3×50 ml of CH₂ Cl₂. The combinedextracts were dried (MgSO₄), filtered and conc. to yield a solid.Recrystallization from heptane yielded 1.0 g (35%) of4-chloro-5-ethoxycarbonyl-2-methyl-4-isothiazolin-3-one, mp 142-147.Analysis: Calculated for C₇ H₈ ClNO₃ S; C, 37.92; H, 3.65; Cl, 16.01; N,6.31; S, 14.47. Found: C, 38.39; H, 3.81; Cl, 15.49; N, 6.31; S, 14.56.

D. 4,5-Dichloro-2-ethyl-4-isothiazolin-3-one

2-Ethyl-3,4,5-trichloroisothiazolium tetrafluoroborate (14.5 g), 0.048mol) was added in portions to 150 ml of a saturated sodium acetatesolution. The aqueous phase was extracted with 3×50 ml of CH₂ Cl₂. Thecombined extracts were dried (MgSO₄), filtered and concentrated. The oilwas distilled to yield 4.2 g (45%)4,5-dichloro-2-ethyl-4-isothiazolin-3-one, bp 89-92 (0.1 mm). Analysis:Calculated for C₅ H₅ Cl₂ NOS: C, 30.34; H, 2.52; Cl, 35.80; N, 7.07; S,16.20. Found: C, 30.04; H, 2.59; Cl, 36.14; N, 6.99; S, 15.70

E. 2-Methyl-4-isothiazolin-3-one

3-Chloro-2-methylisothiazolium fluorosulfonate (39.2 g, 0.17 mol) wasadded in portions to 100 ml of a saturated sodium acetate solution. Theaqueous solution was extracted with 3×50 ml of CH₂ Cl₂. The combinedextracts were dried (MgSO₄), filtered and concentrated. The oil wasdistilled to yield 10.4 g (53%) of 2-methyl-4-isothiazolin-3-one, bp 85°(1.0 mm).

F. 2-Ethyl-4-isothiazolin-3-one

3-Chloro-2-ethylisothiazolium ethylsulfate (15.4 g, 0.56 mol) was addedto 75 ml of a saturated sodium acetate solution. The water was removedat reduced pressure and the residue extracted with 3×50 ml of CH₂ Cl₂.The combined extracts were dried (MgSO₄), filtered and concentrated.Distillation yielded 3.6 g (50%) of 2-ethyl-4-isothiazolium-3-one, bp 92(0.5 mm).

G. 4,5-Dichloro-2-methyl-4-isothiazolin-3-one

2-Methyl-3,4,5-trichloroisothiazoliumfluorosulfonate (5.8 g, 0.02 mol)was added to 100 ml of MeOH and refluxed for 1 hr. The MeOH was removedon a rotary evaporator and the solid collected and washed with water toyield 1.5 g of 4,5-dichloro-2-methyl-4-isothiazolin-3-one.

H. Other 4-Isothiazolin-3-ones

Other 2-alkenyl 4-isothiazolin-3-ones may be similarly prepared from thecorresponding salts by methods as illustrated above.

We claim:
 1. A 4-isothiazolin-3-thione of the formula: ##STR16##wherein: R is selected from the group of alkyl radicals having one toeight carbon atoms or is an allyl group;Y and Z are selected from thegroup consisting of hydrogen, and chlorine, but if Y is the same as Z,both are chlorine.
 2. A compound according to claim 1 wherein R isselected from the group consisting of methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl and allyl.
 3. A compound accordingto claim 1 wherein Y and Z are chlorine.
 4. A compound according toclaim 1 wherein Y is chlorine.
 5. A compound according to claim 4 of theformula ##STR17##
 6. A compound according to claim 3 of the formula##STR18##
 7. A compound according to claim 3 of the formula ##STR19##